Structure Activity Relationships

Alterations in structure, whether done by chemical synthesis or biosynthesis, result in variations in the biological properties of the compound in comparison with the parent. Such SAR reveal the areas of a given structure type that are optimal for driving the potency or selectivity of the series. A very simple example of SAR observed in naturally occurring congeners is illustrated in Figure 6.14 for the antibiotic mannopeptimycin. The mannopeptimycins are ordinarily produced as a mixture of components, some of which contain an isovaleryl ester group on the terminal unit of the di-mannose side chain. The bioassay data in the table are measures of antibiotic effectiveness. Minimal inhibitory concentration values (MIC) are measures of antibiotic potency in vitro that are determined by serial dilution of a solution of antibiotic substance to the point where no inhibition of growth is obtained. This value is reported in terms of a concentration in this case in micrograms per milliliter of the final test solution. The ED50 value refers to the potency of the compound against an infection induced in a mouse model. The lowest concentration of the dose that was still effective in protecting the mouse is shown. The units are in milligrams of antibiotic per kilogram weight of a mouse. What we are able to discern from these data is that the ester function is responsible for conferring a great deal of the potency to the compounds, as alpha is considerably less potent than any of the esterified components. In addition, the position of the ester group on the terminal mannose unit also has a

W-Man

D-Tyr

L-Ser

L-Ser

NH HN

D-Tyr

NH HN

Congener

R Group

MIC ( ng/mL) S. aureus

ED50 (iv, mg/kg) Mouse, S. aureus

HOS^O^f ""OH OH OH

>64

20

V

8

3.5

OH OH

4-8

2.6

OH OH

4

0.6

708

HO ¡u |M)H OH OH

0.5-1

0.04

FIGURE 6.14 Structure-activity relationships in the mannopeptimycin antibiotics.

FIGURE 6.14 Structure-activity relationships in the mannopeptimycin antibiotics.

significant effect on potency with the epsilon component having the ester at the 4'-position being the most potent. These data provide key insights for the design of semisynthetic and biosyntheti-cally derived analogs in a lead optimization program. In the case of mannopeptimycin this initial natural SAR led to the semisynthesis of numerous lipophilic derivatives on the terminal di-mannose moiety. One of the most potent is shown as compound 708 in Figure 6.14. This compound is one of a series of cyclic acetals that showed remarkably enhanced potency as well as presenting excellent chemical and metabolic stability.

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